3-oxygenated 16-hydroxy-d-homopregnen-20-ones and their esters



Unite States Patent 3-0XYGENATED ld-HYDROXY-D-HOMOPREG- NEN-20-ONES ANDTHEIR ESTERS Raymond M. Dodson, Park Ridge, and Paul B. Sollman,Evanston, Ill., assignors, by mesne assignments, to G. D. Searle & Co.,Skokie, 11]., a corporation of Delaware No Drawing. Application November24, 1954 Serial No. 471,118

10 Claims. (Cl. 260-488) The present invention relates to a new group ofchrysene derivatives and, more specifically, to 3-oxygenated16-hydroxy-D-homopregnen-ZO-ones and their esters.

The compounds which constitute this invention can be represented by thegeneral structural formula O CH;

wherein one of the bonds linking the carbon atom in position 5 to thecarbon atoms in positions 4 and 6 is unsaturated, wherein R is a memberof the class consisting of hydrogen and acyl radicals derived frombydrocarbon carboxylic acids containing preferably no more than 8 carbonatoms, and wherein X: is a member of the class consisting of OX0,

radicals, R being defined as R. The acyl radicals which R and R canrepresent are derived from such hydrocarbon carboxylic acids as formic,acetic, propionic, butyric, pentanoic, hexanoic, benzoic, toluic,cyclohexanecarboxylic, cyclohexaneacetic, cyclopentanepropionic acid andthe like.

The compounds of this invention can be synthesized by a method describedin the copending application of R. M. Dodson, Serial No. 362,955, filedJune 19, 1953, which issued as U. S. Patent No. 2,697,109 on December14, 1954. The present application is a continuationin-part of the saidcopending application. The reaction can be illustrated graphically asfollows, showing only ring D and the substituents thereon:

and

Both the 16(1- and 1618-hydroxy isomers are formed.

products in this reaction are the ld-hydroxymethylpregnenes of the type17-dehydro-D-homopregnenes of the type CHzOH and 16-methyl-16-pregnenesof the type The 16-aminomethylpregnenes which serve as startingmaterials in this process are described in detail in the copendingapplication of R. M. Dodson, Serial No. 449,789,v filed August 13, 1954,issued as Patent No. 2,727,908, and Serial No. 458,252, filed September24, 1954.

The compounds of this invention have valuable pharmacologicalproperties. In particular, they offer potent hypotensive agents andantiinflammatory agents. They have a cortisone-like action in suchallergic conditions as iritis. 1

The compounds which constitute this invention and the methods for theirpreparation will appear more fully from the consideration of thefollowing examples. However, the invention is not to be construed aslimited by the details set forth in spirit or in scope. In theseexamples temperatures are indicated in degrees Centigrade and quantitiesof materials in parts by weight. Optical rotations are determined at 25C 7 Example 1 97 parts of 3B-acetoxy-16-aminomethyl-S-pregnen-Z0- oneare dissolved in a solution of 15.7 parts of acetic acid in 1000 partsof water, treated with a solution of 18 parts of sodium nitrite in 2200parts of water and heated on the steam bath for 2 hours. The precipitateis collected on a filter, Washed thoroughly with water and then dried. Asmall amount of additional material is obtained by heating the filtratean additional 4 hours.

The neutral products are hydrolyzed by heating for one hour at refluxtemperature with 50 parts of potassium hydroxide in 250 parts of waterand 1000 parts of methanol. The resulting solution is diluted withwater, neutralized with acetic acid and then filtered. The residue isdissolved in a large volume of a20% solution of ethyl acetate in benzeneand applied to a chromatography column containing 6800 parts of silicagel. The unabsorbed material and that eluted with 20% ethyl acetate in-benzene is chromatographed on a second column containing 2600 parts ofsilica gel. Elution of the second column with a solution of ethylacetate in benzene, concentration of the eluate and crystallization ofthe residue from dilute acetone and then from benzene yields3-hydroxy-D-homo-5,17-pregnadien-20-one," melting at about 231-233" C.The ultraviolet absorption spectrum shows a maximum at 233 milliniicronswith a molecular extinction coefiicient of 8930F'Further elution of thecolumn with a 5% solution of ethyl acetate in benzene yields a compoundC H O the ultraviolet absorption spectrum shows a maximum at 251'millimicrons with an extinction coeflicient of 6900. This compound isprobably impure 3-hydroxy-l6-methyl-5,l6-pregnadien-20- one.

The first column is washed with 80,000 parts of a 20% solution of ethylacetate in benzene and. then eluted with 60,000 parts of a 40% solutionof ethyl acetate in benzene. Concentration of eluate and crystallizationof the residue from dilute dipxane and then from a mixture of benzeneand alcohol yields a compound melting at about 273274.5 C. It, shows noappreciable absorption in the ultraviolet spectrum between 220 and 300millimicrons. This compound has been identified as3,1G-dihydroxy-D-homo-5-pregnen-20-one of the structural formula e t n ifin y rom. d ute m an n rechromatograpliy on alumina yields crystalsmelting at about- 217-220 'C., that have been tentatively identified as:hYd Xy t :5-pr gaep eok ne- Elution of the colurnnu'lith a 50%solutionof ethyl acetate in' benzene a'nd'then with a 75% solution oflethyl acetate in benzene, evaporation of the eluates andcrystallization from acetone yields two crops, the first of which meltsat about 192-202 C. anduthersecond'of which melts at about 20 6f 2q9f C."The second crop is crystal lized, 'once from dilute methanol three tiines from a, mixture of benzene and ethanol. The res'ulting'product meltsat about 216-217 C.- The specific rotation of a 1%.chloroformlsolutionjs [a1 2O This product is presumably due of-i theisomers. of 3,16-d ihfydroxy-D; homo-5-pregnen-20-one, "A mixture with;the isomeric compound, abov'e, 217-52 20 C, manganese; zo l ExqmpleZ A.solution. of 97.parts of 3-acetoxy-16-aminomethyl-5-- pregnen-20-one and15.7 1':-arts of acetic acid in 1000 parts ot water is treated with asolution of 18 parts of sodiumjnitrite in 2200 parts of water and heatedon the steam bath for 2.hours. The precipitate is collected on a filter,washed thoroughly with water and then dried. A. small amount ofadditional material is obtained by further, heatingof the filtrate for 4hours.

The neutral productsare hydrolyzed by heatingfor: one hour at refluxtemperature.witl136,pmts.o sodium hydroxide in 25 0 parts oiwater.and.l000 parts ofmeth- .4 anol. The resulting solution is diluted withwater, neutralized with acetic acid and then filtered. The residue isdissolved in a mixture of 980 parts of pyridine and 810 parts of aceticanhydride. After 16 hours of standing at room temperature, 100 parts ofsolvent are distilled ofi under reduced pressure and the residue ispoured onto 400parts of ice. The precipitate is collected on a filter,washed with water and dried in an oven. It is then dissolved in benzeneand applied to a chromatography column containing 6500. parts of silicagel. Elution with a 2% solution of ethyl acetate in benzene,concentration of the eluate and crystallization of the residue from amixture of ethyl acetate and petroleum ether yields 3-acetoxy-D-homo-S,l7-pregnadien-20rone which melts at about 180-181 C. Thespecific rotation of a 1% chloroform solution is oz =+20.5 Anultraviolet absorption maximum at 233 millimicrons has a molecularextinction coeflicient of about 9,250. Further elution of thev columnwith a 5%. solution oi ethyl. acetate in benzene yields3-acetoxyel6-methyl-5,1-6 pregnadien-20rone, melting at about 1.757116C; The ultraviolet absorption spectrum shows a at 25.1, millimicronswith a molecular extinction coefiicient of about 9,360. An 0.5% ethanolsolution shows a specifigrotation of u =-73.

Further elution oi; the column with a 7% solution of ethyl acetate inbenzene yields 3,16-diacetoxy-D-homo- 5-pregnen-20-one which melts a tabout 2l22l4 C. The

specific rotation of an 0.5% chloroform solution is Further elution-oithe column with a 7% solution of ethyl acetate in benzene yields asubstance melting at about l34l36 C.

Example 3 A solution of 10 parts of" 3,lfi dihydroxy-D-homo-5- regnen-ZO-one in 200 parts of pyridineand 200 parts of acetic anhydride ispermitted to stand at room temperaturefor 16; hours and then poured intoice water. The precipitate is collected on a filter, washed with waterand recrystallized from ethanol to yield 3,16-diacetoxy-D-homo-S-pregnen-ZQ-one melting at about 2l22l4 C. The compound has thestructural formula Example 4 parts of 3-acetox-y-lo-aminomethyl-5-pregnen-20- one;are dissolved ina;solution of'15-.7 partsof acetic acidin IOOO-partsofiwater, treatedwith a solutionof l8-parts-of sodiumnitrite-in ZZOO parts-of water and heatedonthesteam bathtor 2'hours The precipitate iscollec ted:on a filter,washed thorougbly'with water anddried-.= The dried precipitate isdissolved in 3500 parts of benzene andapplied to a chromatography columncontaining 4000 parts of silica gel. Elution with 40,000 parts of a 5%solution of ethyl acetate in benzene yields a (mixture of olefinicmaterials. The column is then eluted with 20% ethyl acetate in benzene.The fractions ,containing solid residues are-crystallized from benzeneand petroleum ether and ,then from aqueous methanol-to yield3-acetoxy-16-hydroxy-D-homo-5- pregnen-ZO-one, melting at about 192-l93C. An 0.8% chloroform solution of this compound shows a specificrotation. [a] :17.3 1

The infrared absorption spectrum shows absorptionmaxima at about 3.38,5.78, 6.96, 7.31, 8.00 and 9.63

microns. It does not show the characteristic aldehyde absorption band inthe neighborhood of 3.6 microns which confirms that the startingmaterial is a D-homopregnen-16-ol rather than a16-hydroxyrnethy1pregnene derivative.

Example 7 To a solution of 1 part of 3,l6-dihydroxy-D-homo5-pregnen-20-one in a minimum of pyridine are added 2 parts offl-cyclopentanepropionyl chloride and the mixture is maintained at C.for 36 hours. The mixture is then diluted with ether, washedsuccessively with water, 5% aqueous sodium hydroxide, and again withwater, dried over anhydrous calcium sulfate, filtered and evaporated toyield the 3,16-bis(fi-cyclopentylpropionyloxy)-D-homo-5-pregnen-20-onewhich shows infrared maxima at 5.77, 5.90, 7.37, and a broad band at8.00 to 8.17 microns. The compound has the structural formula 117 partsof this ester are refluxed for 80 minutes with 9200 parts of2,4,6-collidine. The solution is then poured into 71,000 parts of etherand the ether solution is washed with dilute hydrochloric acid solution,with dilute sodium carbonate solution and with water. The ether solutionis then dried and the solvent is distilled. The residue is crystallizedfrom petroleum ether and then aqueous methanol to yield3acetoxy-Dhomo-5,l7- pregnadien-ZO-one melting at about 179- 181 C.

Example 6 To a mixture of 370 parts of chromium trioxide in 15,000 partsof cold pyridine are added 370 parts of3-acetoxy-16-hydroxy-D-homo-5-pregnen20 one. The resulting solution iskept at room temperature for 24 hours and then poured into 150,000 partsof water. The resulting dark solution, which contains some suspendedsolid material, is extracted portionwise with a total of 400,000 partsof a mixture containing equal volumes of ether and benzene. The combinedorganic layers are washed with water, dried over sodium sulfate anddistilled. The residue is crystallized successively from aqueousmethanol, from ethyl acetate and petroleum ether and from ether andpetroleum ether to yield 3 -acetoxy-D-homo-S-pregnene-16,20-dionemelting at about 166-168 C. The compound has the structural formula COCH3 CHx-COO Examp e 8 Substitution of an equal amount of benzoylchloride for the fl-cyclopentanepropionyl chloride used in the precedingexample yields the 3,16-dibenzoyloxy-D-homo-5- pregnemZO-one which showsinfrared maxima at 5.81, 5.90, 7.36, and 7.80 microns. It has thestructural formula O-C OCaH5 CdHtS-C O O-C'Q Example 9 An anhydroussolution of 5 parts of 3,16-dihydroxy- D-homo-S-pregnen-ZO-one in 500parts of toluene is treated with parts of cyclohexanone and a solutionof 2.5 parts of aluminum isopropoxide in 100 parts of toluene. Themixture is heated under reflux for 30 minutes, cooled and then pouredinto 2500 parts of a saturated aqueous Rochelle salt solution. Theorganic layer is separated, dried over anhydrous sodium sulfate,filtered and concentrated to a small volume. The residue is then appliedto a silica gel chromatography column. The column is washed with benzeneand increasing concentrations of ethyl acetate in benzene. A solution of40% of ethyl acetate in benzene elutes the 16-hydroxy-D-homo-4-pregnene-3,20-dione which is crystallized from a mixture of acetoneand cyclohexane. The crystals thus ob- Example 10 A soiuti'on of-190:parts of 1raminomethylprogesterone in- 3'1"parts ofacetic acid and2000 parts ofwater is treatedzwith asolution of 36z-parts of sodium.nitrite in 2500 .parts. of'water; The mixture. is heated on a steam bathfor 2 hours and then cooled and the precipitate. is collected on afilter, washed with water and dried. A benzene solution of this productis applied to a silica gel chromatography column which is eluted withincreasing concentrations of ethyl acetate in benzene. A 40% solution ofethyl acetate-in benzene gives an eluate which, on concentration, yields16-hydroxy-D-homo-4- pregnene-3,20-dione. On recrystallization fromacetone and cyclohexane, the crystals melt at about 207-209 C.

Whatis claimed is:

1,; Anrember of the class: consisting of 3,16-dihydroxy-D-horno=-pregnen-20-one, 16 hydroXy-D-horno-4-pregnone-3,20-dione andtheir esters of hydrocarbon carboxylic acids containing no more than 8carbon atoms.

2. 3,1G-dihydroxy-D-homo-S-pregnen-20-one.

3. A 3,16-di(lower alkanolyoxy)-D-homo-5-pregnen- 20-one.

4; 3,16-diacetoxy-D-homo-5-pregnen-20-one.

5'. A 3 (lower alkanoyloxy) 16 hydroxy-D-homo-S- pregnen-20 one;

6. 3-acetoxy-lfi-hydroxy-D-homo-S-pregnen-ZO-one.

7; 1.6ehydroxy-D-homo-4-pregnene-3,20rdione.

The-compound has;

8. The process of preparing a cpmpound of the strucr l for ulawherein Ris a member of the class consisting of hydrogen andhydrocarbon-carbonyl' radicals of no more than 8 carbon atoms whichcomprises heatingof a compound of the structural formula O CH:

Hr-NHL' References Cited in the file ofwthis' patent;

UNITED; STATES PATENTS.

2,3 245881 Ruzicka et al.'. July '20, 1943' 2;35 1,637 Ruzicka et al.June 20, 1944- 2 697;109 Dodson Dec; 14; 1954"

1. A MEMBER OF THE CLASS CONSISTING OF3,16-DIHYDROXYD-HOMO-5-PREGNEN-20-ONE, 16-HYDROXY-D-HOMO-4-PREGNENE,3,20-DIONE AND THEIR ESTERS OF HYDROCARBON CARBOXYLIC ACIDS CONTAININGNO MORE THAN 8 CARBON ATOMS.